Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases

BMC Medical Genomics - Tập 13 - Trang 1-13 - 2020
Maria Yamasaki1, Takashi Makino2, Seik-Soon Khor3, Hiromi Toyoda3,4, Taku Miyagawa5, Xiaoxi Liu6, Hitoshi Kuwabara7, Yukiko Kano8,9, Takafumi Shimada10, Toshiro Sugiyama8, Hisami Nishida11, Nagisa Sugaya12, Mamoru Tochigi13, Takeshi Otowa14, Yuji Okazaki15, Hisanobu Kaiya16, Yoshiya Kawamura17, Akinori Miyashita18, Ryozo Kuwano18,19, Kiyoto Kasai20, Hisashi Tanii21, Tsukasa Sasaki22, Makoto Honda5, Katsushi Tokunaga3,4
1Department of Health Data Science Research, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Medical Center, Tokyo, Japan
2Laboratory of Evolutionary Genomics, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
3Genome Medical Science Project (Toyama), National Center for for Global Health and Medicine, Tokyo, Japan
4Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
5Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
6RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
7Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan
8Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan
9Department of Child Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
10Division for Counseling and Support, The University of Tokyo, Tokyo, Japan
11Asunaro Hospital for Child and Adolescent Psychiatry, Mie, Japan
12Unit of Public Health and Preventive Medicine, School of Medicine, Yokohama City University, Kanagawa, Japan
13Department of Neuropsychiatry, Teikyo University Hospital, Tokyo, Japan
14Department of Neuropsychiatry, NTT Medical Center Tokyo, Tokyo, Japan
15Department of Psychiatry, Koseikai Michinoo Hospital, Nagasaki, Japan
16Panic Disorder Research Center, Warakukai Med Corp, Tokyo, Japan
17Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan
18Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan
19Asahigawaso Research Institute, Asahigawaso Medical-Welfare Center, Okayama, Japan
20Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
21Center for Physical and Mental Health, Mie University, Tsu, Japan
22Division of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan

Tóm tắt

Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.

Tài liệu tham khảo

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